We have extended our work on theoretical, experimental, and computational aspects of light -tissue interactions for non- invasive quantitative optical imaging systems. Our methodology known as time-dependent contrast functions, has been validated on several new sets of data provided by our collaborators at Politectico di Milan and University of Florence. Based on these successful quantifications of the absorption and scattering coefficients of abnormal targets (mimicking tumors in otherwise normal tissue), we have recently started a collaboration with researchers at the University of Berlin who have provided in-vivo measurements on human breast, on which our theoretical algorithm based on time-dependent contrast functions will be used to quantify the size and the optical properties of the normal tissue background and those of the tumor. To this end we have successfully deconvoluted the effects of thickness variations and those of the actual width of the incoming pulse from the raw data. In order to avoid incisional biopsy in the oral cavity, a theoretical framework has been developed to quantify the thickening of the epithelial layer in oral mucosa non-invasively. The device which uses an oblique angle reflectance setting is under development and will be used in a Phase II clinical trial (designed by NCI) for the non-invasive study of inflammation and effects of chemopreventative drugs. We are pursuing the use of exogenous and endogenous fluorescent markers to be able to achieve specificity of the spectroscopic signatures of the tissue abnormality under investigation. In collaboration with the University of Tel-Aviv, we have been awarded a BSF grant to continue our research on practical implementation of our previously developed 3D reconstruction algorithm which localizes the position and the concentration of fluorophore masses. We have shown successfully how our inverse algorithm can identify the position and the concentration of two fluorescent targets not seen in the raw data. Along these line of research, we have devised an analytical theory of photon migration to retrieve the life-time of biological analytes. We have started a collaboration with researchers at NCI to study the practical use of our photon migration theory in the development of a guided biopsy infrared fluorescence imaging system for sentinel node detection in breast cancer using fluorescent particles. - Photon Migration Optical Imaging Tissue Optics Tissue Spectroscopy Diffuse Tissue Fluorescence - Human Subjects